Association Of DNA Repair Genes Polymorphisms And The Risk Of Bladder Cancer

Objective: Balance of DNA damage and proper repair plays an important role in progression of bladder cancer.Here we aimed to assess the associations of nineteen polymorphisms from seven DNA repair–associated genes(PARP1,OGG1,APEX1,MUTYH,XRCC1,XRCC2 and XRCC3)with bladder cancer and their interactions in the disease in a Han Chinese population.Methodology/Principal Findings: A chip-based Taq Man genotyping for the candidate genes was performed on 227 bladder cancer patients and 260 healthy controls in Gansu province of China.APEX1 rs3136817,MUTYH rs3219493,three SNPs(rs3213356,rs25487 and rs1799782)in XRCC1,and three SNPs(rs1799794,rs861531 and rs861530)in XRCC3 showed significant associations with the risk of bladder cancer.In APEX1 rs3136817,compared to the TT genotype and T allele,TC genotype and C allele were associated with a decreased risk of bladder cancer(P = 0.002,adjusted OR = 0.48,95% CI: 0.30-0.77;P = 0.005,adjusted OR = 0.56,95% CI: 0.38-0.84,respectively).In MUTYH rs3219493,compared to the C allele,G allele was associated with an increased risk of bladder cancer(P = 0.002,adjusted OR = 1.80,95% CI: 1.24-2.61).In XRCC1 rs3213356,compared to TT genotype,CT genotype showed a decreased risk while CC genotype showed an increased risk of bladder cancer(P = 0.002,adjusted OR = 0.43,95% CI: 0.25-0.74;P = 0.005,adjusted OR = 5.76,95% CI: 1.69-19.67,respectively).In XRCC1 rs25487,compared to the CC genotype,CT genotype was associated with a decreased risk of bladder cancer(P = 0.002,adjusted OR = 0.48,95% CI: 0.31-0.76).In XRCC1 rs1799782,compared to the GG genotype,AA genotype was associated with an icreased risk of bladder cancer(P = 0.005,adjusted OR = 2.67,95% CI: 1.35-5.26.In XRCC3 rs1799794,compared to the TT genotype,TC genotype showed an association with decreased risk of bladder cancer(P = 0.001,adjusted OR = 0.33,95% CI: 0.20-0.55).In XRCC3 rs861531,compared to the CC genotype,AC genotype showed an association with a decreased risk of bladder cancer(P = 0.008,adjusted OR = 0.47,95% CI: 0.27-0.82).XRCC3 rs861530 CT genotype showed a decreased risk of bladder cancer compared to TT genotype(P = 0.002,adjusted OR = 0.48,95% CI: 0.30-0.78).In haplotype analysis,elevated risks of bladder cancer were observed in those with either haplotype GT(OR = 1.56,P = 0.003)of APEX1,or GGGTC(OR = 2.05,P = 0.002)of XRCC1,whereas decreased risks were in individuals with either GCGCC(OR = 0.40,P = 0.001),or GCGTT(OR=0.60,P = 0.005)of XRCC1,or CCC(OR = 0.65,P = 0.004)of MUTYH,or TTTAT(OR = 0.36,P = 0.009)of XRCC3.Interaction analysis showed that the two-loci model(rs1799794 and rs861530)was the best with the maximal testing accuracy of 0.701,and the maximal 100% cross-validation consistency(P = 0.001).Additionally,we found that the relative risk of developing a high-grade tumor was higher in carriers of the following variant alleles than in non-carries: XRCC1 rs3213356(P < 0.001,adjusted OR = 1.91,95% CI: 1.22–3.02),MUTYH rs3219493(P < 0.001,adjusted OR = 1.44,95% CI: 1.13–1.62)and APEX1 rs3136817(P < 0.001,adjusted OR = 3.43,95% CI: 1.64–7.51).After stratified by non-muscle invasive baldder cancer subtypes,the relative risk of developing a high risk tumor was lower in carriers of the variant alleles of APEX1 rs3136817 than in non-carries(P < 0.001,adjusted OR = 0.83,95% CI: 0.81-0.90).The relative risks of tumor relapse were low in carriers of the variant alleles of APEX1 rs3136817 and XRCC2 rs3218454 compared with non-carriers(P < 0.001,adjusted OR = 0.73,95% CI: 0.64-0.80;P < 0.001,adjusted OR = 0.72,95% CI: 0.63-0.82,respectively).After FDR correction for multiple testing,these associations were still significant(QFDR< 0.05).When combined with clinicopathological factors,Patients carrying the variant allele for the XRCC2 rs3218408 polymorphism showed a significantly longer survival than non-carriers(P = 0.04;HR = 0.11,95% CI: 0.01-0.93).Conclusion: Polymorphisms and haplotypes of DNA repair genes are associated with the risk of bladder cancer,and of which the SNPs(rs1799794 and rs861530)in XRCC3 gene might be two major loci in relation to the susceptibility to bladder cancer and several SNPs of DNA repair genes were identified that can influence clinical feature and the prognoses of patients with bladder cancer in Chinese population.